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1.
Toxicol Appl Pharmacol ; 408: 115263, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33022283

RESUMO

Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat because there are no targeted therapies. Currently, chemotherapy is the only clinical option for TNBC despite development of resistance. New therapeutic agents with unique mechanisms of action are urgently needed; therefore, this study investigated the potential anti-TNBC effects of budlein A methylacrylate (BAM), a natural sesquiterpene lactone isolated from plants of the Helianthus genus. We discovered that BAM selectively suppressed and induced apoptosis TNBC cell growth versus other breast cancer or normal mammary epithelial cells. Mechanistically, BAM co-inhibited inhibitor of nuclear factor κBα (IκBα) kinase subunit ß (IKKß) and exportin-1 (XPO-1; chromosome region maintenance 1, CRM1), which are two dysregulated onco-related proteins in TNBC cells, by covalently modifying key functional cysteine residues (Cys179 of IKKß, Cys528 of XPO-1). Dual inhibition led to the stabilization and nuclear retention of IκBα, impairment of NF-κB transcriptional activity, and consequent induction of TNBC cell apoptosis. In conclusion, this study provides evidence that co-inhibition of IKKß and XPO-1 by BAM was effective against TNBC, demonstrating it as a representative new generation inhibitor with potential for TNBC treatment.


Assuntos
Antineoplásicos/uso terapêutico , Quinase I-kappa B/antagonistas & inibidores , Carioferinas/antagonistas & inibidores , Lactonas/uso terapêutico , Metacrilatos/uso terapêutico , Sesquiterpenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Quinase I-kappa B/genética , Carioferinas/genética , Lactonas/farmacologia , Metacrilatos/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , RNA Interferente Pequeno/genética , Sesquiterpenos/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
2.
Toxicology ; 445: 152599, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32976958

RESUMO

Ginkgolide B (GB), a main constituent of Ginkgo biloba extracts, reduces hepatic lipid accumulation and ameliorates nonalcoholic fatty liver disease (NAFLD) in obese mice, but the potential mechanism is unclear. Here we investigated the attenuated effects of GB on the disorder of lipid metabolism, oxidative stress and iron deposition in NAFLD and its potential mechanism associated with ferroptosis. Our preliminary research focused on high fat diet (HFD)-induced ApoE-/-mice gavaged with GB (20 and 30 mg kg-1•d-1, approximately equal to the human dose of 2 and 3 mg kg-1•d-1, respectively) and palmitic acid and oleic acid (PA/OA)-induced HepG2 cells treated with GB (4, 8, 16 µg/mL), respectively. Hepatic injury was assessed via biochemical, histopathological and immunohistochemical evaluations. In order to examine the mechanism of GB on ferroptosis-regulated pathway, we analyzed the expression levels of ferroptosis-related proteins, including nuclear factor erythroid 2 (Nrf2), glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), transferrin receptor-1 (TFR1) and ferritin heavy chain-1 (FTH1) in vivo and vitro experiments by Western blotting. In order to further verify the correlation pathway of ferroptosis, after Nrf2 short hairpin RNA interference, we analyzed the effects of GB on Nrf2 pathway. Both HFD-fed mice and PA/OA-induced HepG2 cells displayed ferroptosis-based panel of biomarkers such as iron overload with the up-regulation of TFR1 and the down-regulation of FTH1, lipid peroxidation and inhibition of Nrf2 activity, which further induced GPX4 and HO-1 levels. Remarkably, after Nrf2 interference, GB treatment significantly increased Nrf2 expression, indicating that GB exerted anti-ferroptosis effects by activation of Nrf2 pathway. Our results are preliminarily illustrated that GB treatment has a specific effect on lipid accumulation and oxidative stress caused ferroptosis in NAFLD, possibly through Nrf2 signaling pathway.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ferroptose/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Ginkgolídeos/uso terapêutico , Lactonas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Ferroptose/fisiologia , Fibrinolíticos/farmacologia , Ginkgolídeos/farmacologia , Células Hep G2 , Humanos , Lactonas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia
3.
Phytother Res ; 34(11): 3029-3040, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32510717

RESUMO

Securinine (Sec) is a naturally derived compound separated from the roots of Securinega suffruticosa, which has long been used as a herbal medicine. Sec is widely known as a GABA receptor antagonist, it is also known as an innate immune cell agonist and has been reported to increase macrophage activity and promote monocyte maturation. On the basis of these studies, we investigated the effect of Sec on osteoclast differentiation and bone resorbing function. We have found that Sec inhibits RANKL-induced osteoclast differentiation, fusion, actin ring formation, and bone resorbing function by the inhibition of gene expression associated with each stage. Moreover, Sec significantly suppressed osteoclastogenesis by decreasing the phosphorylation of p38, Akt, JNK, IκB, and PLCγ2, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos and NFATc1. Finally, Sec effectively protected bone loss induced by the excessive inflammatory responses and activity of osteoclasts in vivo by a micro-CT and histological analysis. In conclusion, our findings suggest that Sec may be a promising drug for bone metabolic diseases such as osteoporosis, which is associated with the excessive activity of osteoclasts.


Assuntos
Azepinas/uso terapêutico , Doenças Ósseas Metabólicas/tratamento farmacológico , Medicina Herbária/métodos , Compostos Heterocíclicos de Anel em Ponte/uso terapêutico , Lactonas/uso terapêutico , Osteogênese/efeitos dos fármacos , Piperidinas/uso terapêutico , Animais , Azepinas/farmacologia , Doenças Ósseas Metabólicas/patologia , Diferenciação Celular , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Humanos , Lactonas/farmacologia , Camundongos , Piperidinas/farmacologia
4.
PLoS Negl Trop Dis ; 14(5): e0008295, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32379762

RESUMO

Genetic epidemiology can provide important insights into parasite transmission that can inform public health interventions. The current study compared long-term changes in the genetic diversity and structure of co-endemic Plasmodium falciparum and P. vivax populations. The study was conducted in Papua Indonesia, where high-grade chloroquine resistance in P. falciparum and P. vivax led to a universal policy of Artemisinin-based Combination Therapy (ACT) in 2006. Microsatellite typing and population genetic analyses were undertaken on available isolates collected between 2004 and 2017 from patients with uncomplicated malaria (n = 666 P. falciparum and n = 615 P. vivax). The proportion of polyclonal P. falciparum infections fell from 28% (38/135) before policy change (2004-2006) to 18% (22/125) at the end of the study (2015-2017); p<0.001. Over the same period, polyclonal P. vivax infections fell from 67% (80/119) to 35% (33/93); p<0.001. P. falciparum strains persisted for up to 9 years compared to 3 months for P. vivax, reflecting higher rates of outbreeding in the latter. Sub-structure was observed in the P. falciparum population, but not in P. vivax, confirming different patterns of outbreeding. The P. falciparum population exhibited 4 subpopulations that changed in frequency over time. Notably, a sharp rise was observed in the frequency of a minor subpopulation (K2) in the late post-ACT period, accounting for 100% of infections in late 2016-2017. The results confirm epidemiological evidence of reduced P. falciparum and P. vivax transmission over time. The smaller change in P. vivax population structure is consistent with greater outbreeding associated with relapsing infections and highlights the need for radical cure to reduce recurrent infections. The study emphasizes the challenge in disrupting P. vivax transmission and demonstrates the potential of molecular data to inform on the impact of public health interventions.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Monitoramento Epidemiológico , Lactonas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada/métodos , Feminino , Variação Genética , Técnicas de Genotipagem , Humanos , Indonésia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Epidemiologia Molecular , Plasmodium falciparum/classificação , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/classificação , Plasmodium vivax/genética , Plasmodium vivax/isolamento & purificação , Adulto Jovem
5.
Cochrane Database Syst Rev ; 4: CD011459, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32352165

RESUMO

BACKGROUND: Dementia is a worldwide concern. Its global prevalence is increasing. At present, there is no medication licensed to prevent or delay the onset of dementia. Inflammation has been suggested as a key factor in dementia pathogenesis. Therefore, medications with anti-inflammatory properties could be beneficial for dementia prevention. OBJECTIVES: To evaluate the effectiveness and adverse effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) for the primary or secondary prevention of dementia. SEARCH METHODS: We searched ALOIS, the specialised register of the Cochrane Dementia and Cognitive Improvement Group up to 9 January 2020. ALOIS contains records of clinical trials identified from monthly searches of several major healthcare databases, trial registries and grey literature sources. We ran additional searches across MEDLINE (OvidSP), Embase (OvidSP) and six other databases to ensure that the searches were as comprehensive and up-to-date as possible. We also reviewed citations of reference lists of included studies. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing aspirin or other NSAIDs with placebo for the primary or secondary prevention of dementia. We included trials with cognitively healthy participants (primary prevention) or participants with mild cognitive impairment (MCI) or cognitive complaints (secondary prevention). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the strength of evidence for each outcome using the GRADE approach. MAIN RESULTS: We included four RCTs with 23,187 participants. Because of the diversity of these trials, we did not combine data to give summary estimates, but presented a narrative description of the evidence. We identified one trial (19,114 participants) comparing low-dose aspirin (100 mg once daily) to placebo. Participants were aged 70 years or older with no history of dementia, cardiovascular disease or physical disability. Interim analysis indicated no significant treatment effect and the trial was terminated slightly early after a median of 4.7 years' follow-up. There was no evidence of a difference in incidence of dementia between aspirin and placebo groups (risk ratio (RR) 0.98, 95% CI 0.83 to 1.15; high-certainty evidence). Participants allocated aspirin had higher rates of major bleeding (RR 1.37, 95% CI 1.17 to 1.60, high-certainty evidence) and slightly higher mortality (RR 1.14, 95% CI 1.01 to 1.28; high-certainty evidence). There was no evidence of a difference in activities of daily living between groups (RR 0.84, 95% CI 0.70 to 1.02; high-certainty evidence). We identified three trials comparing non-aspirin NSAIDs to placebo. All three trials were terminated early due to adverse events associated with NSAIDs reported in other trials. One trial (2528 participants) investigated the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib (200 mg twice daily) and the non-selective NSAID naproxen (220 mg twice daily) for preventing dementia in cognitively healthy older adults with a family history of Alzheimer's disease (AD). Median follow-up was 734 days. Combining both NSAID treatment arms, there was no evidence of a difference in the incidence of AD between participants allocated NSAIDs and those allocated placebo (RR 1.91, 95% CI 0.89 to 4.10; moderate-certainty evidence). There was also no evidence of a difference in rates of myocardial infarction (RR 1.21, 95% CI 0.61 to 2.40), stroke (RR 1.82, 95% CI 0.76 to 4.37) or mortality (RR 1.37, 95% CI 0.78 to 2.43) between treatment groups (all moderate-certainty evidence). One trial (88 participants) assessed the effectiveness of celecoxib (200 mg or 400 mg daily) in delaying cognitive decline in participants aged 40 to 81 years with mild age-related memory loss but normal memory performance scores. Mean duration of follow-up was 17.6 months in the celecoxib group and 18.1 months in the placebo group. There was no evidence of a difference between groups in test scores in any of six cognitive domains. Participants allocated celecoxib experienced more gastrointestinal adverse events than those allocated placebo (RR 2.66, 95% CI 1.05 to 6.75; low-certainty evidence). One trial (1457 participants) assessed the effectiveness of the COX-2 inhibitor rofecoxib (25 mg once daily) in delaying or preventing a diagnosis of AD in participants with MCI. Median duration of study participation was 115 weeks in the rofecoxib group and 130 weeks in the placebo group. There was a higher incidence of AD in the rofecoxib than the placebo group (RR 1.32, 95% CI 1.01 to 1.72; moderate-certainty evidence). There was no evidence of a difference between groups in cardiovascular adverse events (RR 1.07, 95% CI 0.68 to 1.66; moderate-certainty evidence) or mortality (RR 1.62, 95% CI 0.85 to 3.05; moderate-certainty evidence). Participants allocated rofecoxib had more upper gastrointestinal adverse events (RR 3.53, 95% CI 1.17 to 10.68; moderate-certainty evidence). Reported annual mean difference scores showed no evidence of a difference between groups in activities of daily living (year 1: no data available; year 2: 0.0, 95% CI -0.1 to 0.2; year 3: 0.1, 95% CI -0.1 to 0.3; year 4: 0.1, 95% CI -0.1 to 0.4; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There is no evidence to support the use of low-dose aspirin or other NSAIDs of any class (celecoxib, rofecoxib or naproxen) for the prevention of dementia, but there was evidence of harm. Although there were limitations in the available evidence, it seems unlikely that there is any need for further trials of low-dose aspirin for dementia prevention. If future studies of NSAIDs for dementia prevention are planned, they will need to be cognisant of the safety concerns arising from the existing studies.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Demência/prevenção & controle , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/prevenção & controle , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Demência/epidemiologia , Demência/mortalidade , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Incidência , Lactonas/uso terapêutico , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Naproxeno/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/epidemiologia , Sulfonas/uso terapêutico
6.
Toxicol Appl Pharmacol ; 401: 115071, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454055

RESUMO

Prostate Cancer (PCa) is the second most common cancer among men in United States after skin cancer. Conventional chemotherapeutic drugs available for PCa treatment are limited due to toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatment for advanced PCa. In this current study, we focused on evaluating the anti-cancer efficacy of Eprinomectin (EP), a novel avermectin analog against PC3 metastatic PCa cells. EP displayed robust inhibition of cell viability of PC3 cells in addition to suppressing the colony formation and wound healing capabilities. Our study showed that EP targets PC3 cells via inducing ROS and apoptosis activation. EP treatment enforces cell cycle arrest at G0/G1 phase via targeting cyclin-dependent kinase 4 (CDK4) and subsequent induction of apoptosis in PC3 cells. At the molecular level, EP effectively inhibited the expression of various cancer stem cell markers such as ALDH1, Sox-2, Nanog, Oct3/4 and CD44. Interestingly, EP also inhibited the activity of alkaline phosphatase, a maker of pluripotent stem cells. Of note, EP treatment resulted in the translocation of ß-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/ß-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4, and c-Myc. In addition, EP inhibited the anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ivermectina/análogos & derivados , Lactonas/farmacologia , Compostos Macrocíclicos/farmacologia , Neoplasias da Próstata/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/fisiologia , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Ivermectina/química , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lactonas/uso terapêutico , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Masculino , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
7.
Vasc Med ; 25(2): 124-132, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32000630

RESUMO

Intensive antithrombotic therapy reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Recent studies have suggested heterogeneity in risk and benefit in those with and without concomitant coronary artery disease (CAD) and peripheral revascularization. We evaluated the risk of MACE and MALE in patients with PAD stratified by history of concomitant CAD and prior peripheral revascularization and whether the efficacy and safety of vorapaxar were similar in these subgroups. The TRA 2°P-TIMI 50 trial randomized 26,449 patients with prior MI, ischemic stroke, or PAD to vorapaxar or placebo. This analysis examined the effect of vorapaxar in a broad population of 6136 patients with PAD. Overall, vorapaxar significantly reduced MACE (HR 0.85, 95% CI 0.73, 0.99; p = 0.034) and MALE (HR 0.70, 95% CI 0.53, 0.92; p = 0.011) in patients with PAD. The absolute risk reduction (ARR) for MACE was greater in patients with PAD and CAD versus those with PAD alone (-2.2% vs 0.1%: number needed to treat (NNT) 45 vs 1000). Conversely, the ARR for MALE was higher in those with prior lower extremity revascularization (2.5% vs 0.2%: NNT 40 vs 500). Vorapaxar increased major bleeding (HR 1.39, 95% CI 1.12, 1.71; p = 0.003). The net clinical outcome in all patients with PAD was reduced with vorapaxar (HR 0.82, 95% CI 0.72, 0.94; p = 0.004), with benefits driven by reductions in MACE for those with CAD and by reductions in MALE for those with prior peripheral revascularization. Among patients with PAD, vorapaxar resulted in a net clinical benefit; however, the drivers of benefit were heterogeneous, with greater reductions in MACE in those with concomitant CAD and greater reductions in MALE in those with prior lower extremity revascularization, and unclear benefit in patients with neither. These clinical characteristics may be useful in identifying the subgroups of patients with PAD most likely to benefit from potent antithrombotic therapies. ClinicalTrials.gov Identifier: NCT00526474.


Assuntos
Doença da Artéria Coronariana/complicações , Fibrinolíticos/uso terapêutico , Lactonas/uso terapêutico , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Piridinas/uso terapêutico , Idoso , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Procedimentos Endovasculares , Feminino , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Lactonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/complicações , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/mortalidade , Inibidores da Agregação de Plaquetas/efeitos adversos , Piridinas/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares
8.
Molecules ; 25(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033280

RESUMO

The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular "machine." As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Proteostase/efeitos dos fármacos , Compostos de Boro/metabolismo , Compostos de Boro/uso terapêutico , Bortezomib/metabolismo , Bortezomib/uso terapêutico , Glicina/análogos & derivados , Glicina/metabolismo , Glicina/uso terapêutico , Humanos , Lactonas/metabolismo , Lactonas/uso terapêutico , Oligopeptídeos/metabolismo , Oligopeptídeos/uso terapêutico , Pirróis/metabolismo , Pirróis/uso terapêutico
9.
Immunopharmacol Immunotoxicol ; 42(2): 84-92, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32064988

RESUMO

Background: Inflammatory response plays a crucial role in the occurrence and development of diabetic nephropathy (DN). Drugs that carry anti-inflammatory effects have the potential to treat diabetic nephropathy. It's reported that alantolactone (ALA), a natural product, has a variety of pharmacological effects against inflammation and oxidation. However, the specific effects of alantolactone on DN and the mechanisms underlying alantolactone remain elusive. Therefore, the present study aimed to probe whether ALA could mitigate inflammation as mediated by high glucose (HG) in NRK-52E cells and reduce renal injury caused by diabetic nephropathy.Materials and methods: The anti-inflammatory effect of ALA was evaluated in the present study using ELISA and RT-qPCR. Western blot and macrophage adhesion assay were then performed to confirm anti-macrophage adhesion and the protein expression of cell adhesion molecules. Finally, the effect of ALA and its underlying mechanism was evaluated in vivo.Results: Results showed that ALA curbed HG-stimulated expression of macrophage adhesion and pro-inflammatory cytokines in renal NRK-52E cells. In addition, both pro-inflammatory cytokines and NF-kappa B witnessed reduced expression or activity in oral administration with ALA in vivo, thus inhibiting the increase of serum creatinine and urea nitrogen (BUN) levels. This in consequence ameliorated fibrosis and stemmed pathological worsening of diabetic renal tissues.Conclusions: These findings suggest that ALA may hold promise in the treatment of DN, and importantly, the anti-inflammatory system may prove to be a new strategy to treat human DN.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/tratamento farmacológico , Lactonas/uso terapêutico , Macrófagos Peritoneais/efeitos dos fármacos , Sesquiterpenos de Eudesmano/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Adesão Celular/imunologia , Linhagem Celular , Citocinas/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Testes de Função Renal , Lactonas/administração & dosagem , Macrófagos Peritoneais/imunologia , Camundongos Endogâmicos C57BL , Ratos , Sesquiterpenos de Eudesmano/administração & dosagem
10.
J Ethnopharmacol ; 252: 112605, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31981749

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Secoeudesma sesquiterpenes lactone A (SESLA) is a sesquiterpene compound isolated from Inula japonica Thunb. (I. japonica). It is an herb widely distributed in Asian countries often used for the treatment of various conditions including tumors, bronchitis and bacterial and viral infections. It has been reported that SESLA could significantly inhibit the production of nitric oxide (NO) by lipopolysaccharide (LPS) in Raw264.7 cells. However, the mechanism responsible for this anti-inflammatory role and its role in the treatment of antibiotic-resistant bacterial infection, e.g., carbapenem-resistant Klebsiella pneumoniae (CRKP), remain to be investigated. AIM OF THE STUDY: This study was carried out to investigate the protective anti-inflammatory role and the underlying molecular mechanisms of SESLA in LPS or CRKP evoked inflammation. MATERIALS AND METHODS: ELISA and PCR were utilized to detect the expression of inflammatory mediators in LPS or heat-killed CRKP (HK CRKP)-stimulated immune cells containing different concentrations of SESLA. The protective role of SESLA was observed in mice challenged with a lethal dose of CRKP. Mice were intraperitoneally injected with CRKP to create a septic mouse model to evaluate the protective role of SESLA in vivo. Phosphorylated proteins, which represented the activation of signaling pathways, were examined by Western blot. RESULTS: SESLA was showed to inhibit the expression of inflammatory mediators in various macrophages and dendritic cells upon stimulation of LPS or HK CRKP. It also facilitated phagocytosis of bacteria by Raw264.7 cells. The combined use of SELSA and the ineffective antibiotic, meropenem, increased the survival rate of CRKP infected mice from 25% to 50%. ERK, NF-κB and PI3K/Akt pathways accounted for the anti-inflammatory role of SESLA with the stimulation of LPS. CONCLUSION: According to the notable anti-inflammatory effect in vitro and its joint protective effects on a septic mouse model, SESLA might act as an adjuvant drug candidate for sepsis, even those caused by antibiotic-resistant bacteria, e.g., CRKP.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae , Lactonas/uso terapêutico , Sepse/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Adjuvantes Imunológicos/farmacologia , Animais , Antibacterianos , Anti-Inflamatórios/farmacologia , Carbapenêmicos , Citocinas/imunologia , Farmacorresistência Bacteriana , Feminino , Inula , Infecções por Klebsiella/imunologia , Lactonas/farmacologia , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Sepse/imunologia , Sesquiterpenos/farmacologia
11.
Biomed Pharmacother ; 121: 109660, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733581

RESUMO

Topiroxostat is a selective xanthine oxidoreductase (XOR) inhibitor for the management of hyperuricemia in patients with or without gout. In this work, we aim to employ the physiologically based pharmacokinetic (PBPK) model with the drug-target residence time model to predict and characterize both the pharmacokinetics (PK) and pharmacodynamics (PD) of topiroxostat in humans. The plasma concentration-time profile of topiroxostat was simulated based on drug properties and human physiology parameters. The predictive power of this PBPK model was then demonstrated by comparison of stimulated to observed pharmacokinetic parameters. The utility of the model was further demonstrated through predicting the oral absorption and disposition characteristics of topiroxostat in humans. Finally, by combining the PBPK model and the drug-target residence time model, we successfully predicted the target occupancy and built the relationship between PK and PD using in vitro, in vivo and in silico information. The results showed that topiroxostat exhibited significant in vivo pharmacological activity even after the complete clearance of this drug from the liver (target site), which may be due to the long residence time of the binary topiroxostat-XOR complex. This work may be helpful to guide future investigations of topiroxostat and also provides a novel strategy for PK/PD studies.


Assuntos
Interações Medicamentosas/fisiologia , Nitrilos/farmacocinética , Nitrilos/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Adulto , Atorvastatina/farmacocinética , Atorvastatina/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Estudos de Avaliação como Assunto , Humanos , Lactonas/farmacocinética , Lactonas/uso terapêutico , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/metabolismo , Rabdomiólise/tratamento farmacológico , Rabdomiólise/metabolismo
12.
Int Immunopharmacol ; 79: 106048, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31863924

RESUMO

Growing evidence suggests that activated immune cells undergo metabolic reprogramming in the regulation of the innate inflammatory response. Remarkably, macrophages activated by lipopolysaccharide (LPS) induce a switch from oxidative phosphorylation to aerobic glycolysis, and consequently results in release of proinflammatory cytokines. Pyruvate Kinase M2 (PKM2) plays a vital role in the process of macrophage activation, promoting the inflammatory response in sepsis and septic shock. Deoxyelephantopin (DET), a naturally occurring sesquiterpene lactone from Elephantopus scaber, has been shown to counteracts inflammation during fulminant hepatitis progression, but the underlying mechanism remains unclear. Here, we studied the function of the DET on macrophage activation and investigated the anti-inflammatory effects of DET associated with interfering with glycolysis in macrophage. Our results first demonstrated that DET attenuates LPS-induced interleukin-1ß (IL-1ß) and high-mobility group box 1 (HMGB1) release in vitro and in vivo and protected mice against lethal endotoxemia. Furthermore, DET decreased the expression of pyruvate dehydrogenase kinase 1 (PDK1), glucose transporter 1(GLUT1), lactate dehydrogenase A (LDHA), and reduced lactate production dose-dependently in macrophages. Moreover, we further revealed that DET attenuates aerobic glycolysis in macrophages associated with regulating the nuclear localization of PKM2. Our results provided a novel mechanism for DET suppression of macrophages activation implicated in anti-inflammatory therapy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Lactonas/uso terapêutico , Macrófagos/imunologia , Piruvato Quinase/metabolismo , Sepse/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Aerobiose , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Glicólise/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Sepse/imunologia , Transdução de Sinais
13.
PLoS One ; 14(12): e0226626, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31877172

RESUMO

Ginkgo biloba leaves extract (GBE) was subjected to neuroprotective-guided fractionation to produce eleven fractions with different polarities and constituents. The intermediate polar fraction was shown to be terpene trilactones-enriched fraction (TEGBE). Out of this fraction, pure ginkgolide B (G-B) was further purified and identified based on its spectral data. The effects of GBE and TEGBE were evaluated in comparison to that of G-B in the crush sciatic nerve injury rat model. To evaluate the neuroprotective effects, sixty Wistar male rats were randomly allocated into 6 groups: naive, sham, crush + normal saline, and three treatment groups; crush + GBE, crush + TEGBE, and crush + G-B. Treatments were given one hour following injury, and once daily for 14 days. Neurobehavioral tests, histomorphological examinations, and immunohistochemical analysis of the sciatic nerve and the spinal cord were performed at weeks 3 and 6 post-injury. GBE, TEGBE and G-B were shown to enhance the functional and sensory behavioral parameters and to protect the histological and the ultrastructural elements in the sciatic nerve. Additionally, all treatments prevented spinal cord neurons from further deterioration. It was shown that G-B has the most significant potential effects among all treatments with values that were nearly comparable to those of sham and naive groups.


Assuntos
Lesões por Esmagamento/tratamento farmacológico , Ginkgolídeos/uso terapêutico , Lactonas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Nervo Isquiático/lesões , Animais , Lesões por Esmagamento/patologia , Masculino , Traumatismos dos Nervos Periféricos/patologia , Ratos Wistar , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia
14.
Oxid Med Cell Longev ; 2019: 4568964, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781335

RESUMO

STAT3 is a nuclear transcription factor that regulates genes involved in cell cycle, cell survival, and immune response. Although STAT3 activation drives cells to physiological response, its deregulation is often associated with the development and progression of many solid and hematological tumors as well as with drug resistance. STAT3 is a redox-sensitive protein, and its activation state is related to intracellular GSH levels. Under oxidative conditions, STAT3 activity is regulated by S-glutathionylation, a reversible posttranslational modification of cysteine residues. Compounds able to suppress STAT3 activation and, on the other hand, to modulate intracellular redox homeostasis may potentially improve cancer treatment outcome. Nowadays, about 35% of commercial drugs are natural compounds that derive from plant extracts used in phytotherapy and traditional medicine. Sesquiterpene lactones are an interesting chemical group of plant-derived compounds often employed in traditional medicine against inflammation and cancer. This review focuses on sesquiterpene lactones able to downmodulate STAT3 signaling leading to an antitumor effect and correlates the anti-STAT3 activity with their ability to decrease GSH levels in cancer cells. These properties make them lead compounds for the development of a new therapeutic strategy for cancer treatment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lactonas/uso terapêutico , Proteínas de Neoplasias/metabolismo , Neoplasias , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Oxirredução
15.
Int J Mol Sci ; 20(22)2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31717963

RESUMO

Protease-activated receptors (PARs) are a family of four GPCRs with a variety of cellular functions, yet the only advanced clinical endeavours to target these receptors for therapeutic gain to date relates to the impairment of platelet function for anti-thrombotic therapy. The only approved PAR antagonist is the PAR1 inhibitor, vorapaxar-the sole anti-platelet drug against a new target approved in the past 20 years. However, there are two PARs on human platelets, PAR1 and PAR4, and more recent efforts have focused on the development of the first PAR4 antagonists, with first-in-class agents recently beginning clinical trial. Here, we review the rationale for this approach, outline the various modes of PAR4 inhibition, and speculate on the specific therapeutic potential of targeting PAR4 for the prevention of thrombotic conditions.


Assuntos
Inibidores da Agregação de Plaquetas/farmacologia , Receptores de Trombina/antagonistas & inibidores , Trombose/tratamento farmacológico , Animais , Plaquetas/efeitos dos fármacos , Humanos , Lactonas/administração & dosagem , Lactonas/farmacologia , Lactonas/uso terapêutico , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/uso terapêutico , Piridinas/administração & dosagem , Piridinas/farmacologia , Piridinas/uso terapêutico , Trombose/metabolismo
16.
Malar J ; 18(1): 364, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718659

RESUMO

BACKGROUND: Long-lasting insecticidal nets (LLIN), improved diagnosis and artemisinin-based combination therapy (ACT) have reduced malaria prevalence in Papua New Guinea since 2008. Yet, national incidence trends are inconclusive due to confounding effects of the scale-up of rapid diagnostic tests, and inconsistencies in routine reporting. METHODS: Malaria trends and their association with LLIN and ACT roll-out between 2010 and 2014 in seven sentinel health facilities were analysed. The analysis included 35,329 fever patients. Intervention effects were estimated using regression models. RESULTS: Malaria incidence initially ranged from 20 to 115/1000 population; subsequent trends varied by site. Overall, LLIN distributions had a cumulative effect, reducing the number of malaria cases with each round (incidence rate ratio ranging from 0.12 to 0.53 in five sites). No significant reduction was associated with ACT introduction. Plasmodium falciparum remained the dominant parasite in all sentinel health facilities. Resurgence occurred in one site in which a shift to early and outdoor biting of anophelines had previously been documented. CONCLUSIONS: LLINs, but not ACT, were associated with reductions of malaria cases in a range of settings, but sustainability of the gains appear to depend on local factors. Malaria programmes covering diverse transmission settings such as Papua New Guinea must consider local heterogeneity when choosing interventions and ensure continuous monitoring of trends.


Assuntos
Artemisininas/uso terapêutico , Controle de Doenças Transmissíveis/estatística & dados numéricos , Instalações de Saúde/estatística & dados numéricos , Mosquiteiros Tratados com Inseticida/estatística & dados numéricos , Lactonas/uso terapêutico , Malária/prevenção & controle , Controle de Mosquitos , Combinação de Medicamentos , Humanos , Incidência , Malária/epidemiologia , Papua Nova Guiné/epidemiologia , Plasmodium/isolamento & purificação
17.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652659

RESUMO

Ivalin, a natural compound isolated from Carpesium divaricatum, showed excellent microtubule depolymerization activities among human hepatocellular carcinoma in our previous work. Here, we investigated its functions on mitochondria-mediated apoptosis in hepatocellular carcinoma SMMC-7721 cells. DAPI (4',6-diamidino-2-phenylindole) staining, annexin V-fluorexcein isothiocyanate (FITC) apoptosis detection, and western blotting were applied to explore the apoptotic effect of Ivalin. Next, the induction effect of Ivalin on the mitochondrial pathway was also confirmed via a series of phenomena including the damage of mitochondria membrane potential, mitochondria cytochrome c escape, cleaved caspase-3 induction, and the reactive oxygen species generation. In this connection, we understood that Ivalin induced apoptosis through the mitochondrial pathway and the overload of reactive oxygen species. Furthermore, we found that the activation of nuclear factor-κB (NF-κB) and subsequent p53 induction were associated with the apoptotic effect of Ivalin. These data confirmed that Ivalin might be a promising pro-apoptotic compound that can be utilized as a potential drug for clinical treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Lactonas/farmacologia , Neoplasias Hepáticas/metabolismo , Mitocôndrias/efeitos dos fármacos , NF-kappa B/metabolismo , Sesquiterpenos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Asteraceae/química , Carcinoma Hepatocelular/tratamento farmacológico , Caspase 3/metabolismo , Linhagem Celular Tumoral , Citocromos c/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Lactonas/química , Lactonas/metabolismo , Lactonas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/química , Sesquiterpenos/metabolismo , Sesquiterpenos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
18.
J Ethnopharmacol ; 245: 112186, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31472273

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sesquiterpene lactones are organic compounds derived mainly from plants that exhibit anti-inflammatory and antitumor activities being one of the key mechanism of action of NF-kB pathway and synthesis of cytokines such as IL-1 and TNF- α. AIM OF THE STUDY: The overall objective of the present study was to evaluate the anti-inflammatory action of a sesquiterpene lactone diacethylpiptocarphol (DPC) from Vernonia scorpioides (Lam.) Pers. and parthenolide (PTH) in Balb-c mice with DSS-induced colitis. MATERIALS AND METHODS: The anti-inflammatory effects of Intraperitonial administration of DPC (5 mg/kg/day) were evaluated in Balb/c mice with DSS-induced colitis, and further the body weight measurement, TNF-α and TGF-ß level was determined. RESULTS: After intraperitoneal treatment for one week, DSS-induced colitis was significantly reduced in mice treated with either of both sesquiterpenes lactones, as witnessed by reduced cellular infiltration, tissue damage, TNF-α production, and enhanced production of TGF-ß. CONCLUSIONS: Sesquiterpene lactone DPC, isolated from Vernonia scorpioides showed anti-inflammatory activity, in this experimental model of colitis the sesquiterpene lactones DPC and PTH exhibit equal anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Lactonas/uso terapêutico , Sesquiterpenos/uso terapêutico , Vernonia , Animais , Colite/sangue , Colite/induzido quimicamente , Colite/patologia , Colo/efeitos dos fármacos , Colo/patologia , Sulfato de Dextrana , Flores , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos BALB C , Folhas de Planta , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue
19.
Anal Cell Pathol (Amst) ; 2019: 1598182, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482051

RESUMO

Human hepatocellular carcinoma (HCC) is the most common and recurrent type of primary adult liver cancer without any effective therapy. Plant-derived compounds acting as anticancer agents can induce apoptosis by targeting several signaling pathways. Strigolactone (SL) is a novel class of phytohormone, whose analogues have been reported to possess anticancer properties on a panel of human cancer cell lines through inducing cell cycle arrest, destabilizing microtubular integrity, reducing damaged in the DNA repair machinery, and inducing apoptosis. In our previous study, we reported that a novel SL analogue, TIT3, reduces HepG2 cell proliferation, inhibits cell migration, and induces apoptosis. To decipher the mechanisms of TIT3-induced anticancer activity in HepG2, we performed RNA sequencing and the differential expression of genes was analyzed using different tools. RNA-Seq data showed that the genes responsible for microtubule organization such as TUBB, BUB1B, TUBG2, TUBGCP6, TPX2, and MAP7 were significantly downregulated. Several epigenetic modulators such as UHRF1, HDAC7, and DNMT1 were also considerably downregulated, and this effect was associated with significant upregulation of various proapoptotic genes including CASP3, TNF-α, CASP7, and CDKN1A (p21). Likewise, damaged DNA repair genes such as RAD51, RAD52, and DDB2 were also significantly downregulated. This study indicates that TIT3-induced antiproliferative and proapoptotic activities on HCC cells could involve several signaling pathways. Our results suggest that TIT3 might be a promising drug to treat HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Lactonas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Lactonas/química , Lactonas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Med Sci Monit ; 25: 6711-6718, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31492830

RESUMO

BACKGROUND Liver cancer is one of the most common malignancies around the world and one of the major causes of cancer related mortality. The objective of this study was to evaluate the anticancer effect of the natural compound psilostachyin-A on 5-fluorouracil-resistant human liver carcinoma cells and its effects on autophagy, cell cycle, caspase activation, and the ERK/MAPK signaling pathway. MATERIAL AND METHODS Cell Counting Kit 8 (CCK-8) assay was used to evaluate the effects on HepG2 cell viability at different doses of psilostachyin-A. Cell cycle analysis was performed using flow cytometry, and Transwell assay was used to check effects on cell invasion. Transmission electron microscopic studies were done to evaluate autophagy induced by psilostachyin-A, and the western blot method was carried out to evaluate the effects on autophagy and the ERK/MAPK signaling pathway. RESULTS CCK-8 assay revealed that the psilostachyin-A reduced the cell viability of HepG2 cancer cells in a dose dependent manner. Psilostachyin-A also reduced the colony forming potential of HepG2 cells, concentration dependently. The IC50 of psilostachyin was found to be 25 µM. The anticancer effects of psilostachyin-A were due to the induction of autophagy which was accompanied by enhancement of LC3B II expression. Psilostachyin also caused cell cycle arrest by enhancing the accumulation of HepG2 cells in the G2/M phase. Transwell assay showed that psilostachyin-A suppressed the invasion of HepG2 cells. The results also showed that psilostachyin-A could block the ERK/MAPK pathway, indicative of the cytotoxic effects of psilostachyin-A on liver cancer. CONCLUSIONS These preliminary observations suggested that psilostachyin-A might prove beneficial in the treatment of liver cancer.


Assuntos
Antineoplásicos/uso terapêutico , Autofagia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fluoruracila/uso terapêutico , Lactonas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Pontos de Checagem da Fase M do Ciclo Celular , Sistema de Sinalização das MAP Quinases , Sesquiterpenos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Proliferação de Células/efeitos dos fármacos , Fluoruracila/farmacologia , Células Hep G2 , Humanos , Lactonas/química , Lactonas/farmacologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/ultraestrutura , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Ensaio Tumoral de Célula-Tronco , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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